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RU2019127316A - RNA-GUIDED HUMAN GENOME ENGINEERING - Google Patents

RNA-GUIDED HUMAN GENOME ENGINEERING Download PDF

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RU2019127316A
RU2019127316A RU2019127316A RU2019127316A RU2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A RU 2019127316 A RU2019127316 A RU 2019127316A
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sequence
nucleic acid
rna
rna guide
guide
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RU2019127316A
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RU2019127316A3 (en
RU2766685C2 (en
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Джордж М. ЧЁРЧ
Прашант МАЛИ
Лухан ЯНГ
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Президент Энд Фэллоуз Оф Харвард Коллидж
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Claims (39)

1. Направляющая РНК, предназначенная для изменения эукариотической клетки, содержащая направляющую последовательность, комплементарную целевой последовательности нуклеиновой кислоты и каркасной последовательности, присоединенной к направляющей последовательности, и каркасную последовательность, причем направляющая РНК содержит от около 100 до около 250 нуклеотидов. 1. Guide RNA, designed to change a eukaryotic cell, containing a guide sequence complementary to the target nucleic acid sequence and a frame sequence attached to the guide sequence, and the frame sequence, and the guide RNA contains from about 100 to about 250 nucleotides. 2. Направляющая РНК по п. 1, отличающаяся тем, что направляющая РНК содержит около 100 нуклеотидов.2. The RNA guide according to claim 1, characterized in that the RNA guide contains about 100 nucleotides. 3. Направляющая РНК по п. 1, отличающаяся тем, что направляющая РНК представляет собой слитый транскрипт crРНК-tracrРНК.3. The RNA guide according to claim 1, characterized in that the RNA guide is a fusion transcript of crRNA-tracrRNA. 4. Направляющая РНК по п. 1, отличающаяся тем, что направляющая РНК представляет собой слитый транскрипт crРНК-tracrРНК, обладающий вторичной структурой, включающей первую шпильку, соединенную со спейсерной последовательностью, и вторую 3’-шпильку.4. The RNA guide according to claim 1, characterized in that the RNA guide is a fusion transcript of crRNA-tracrRNA having a secondary structure comprising a first hairpin connected to a spacer sequence and a second 3’ hairpin. 5. Направляющая РНК по п. 1, отличающаяся тем, что каркасная последовательность включает следующую последовательность нуклеиновой кислоты GUUUUAGAGCUAGAAA UAGCAAGUUAAAAUAA GGCUAGUCCGUUAUCA ACUUGAAAAAGUGGCA CCGAGUCGGUGC (SEQ ID NO:46).5. The RNA guide according to claim 1, wherein the frame sequence comprises the following nucleic acid sequence GUUUUAGAGCUAGAAA UAGCAAGUUAAAAUAA GGCUAGUCCGUUAUCA ACUUGAAAAAGUGGCA CCGAGUCGGUGC (SEQ ID NO: 46). 6. Направляющая РНК по п. 1, отличающаяся тем, что к 3’-концу каркасной последовательности присоединена последовательность поли-U.6. The RNA guide according to claim 1, characterized in that the poly-U sequence is attached to the 3’-end of the frame sequence. 7. Направляющая РНК по п. 1, отличающаяся тем, что последовательность поли-U UUUU присоединена к 3’-концу каркасной последовательности.7. The RNA guide according to claim 1, characterized in that the poly-U UUUU sequence is attached to the 3’-end of the frame sequence. 8. Сконструированная последовательность нуклеиновой кислоты, содержащая нуклеотидную последовательность, кодирующую последовательность направляющей РНК по п. 1.8. The constructed nucleic acid sequence containing the nucleotide sequence encoding the sequence of the RNA guide according to claim 1. 9. Сконструированная последовательность нуклеиновой кислоты по п. 8, дополнительно включающая регуляторный элемент, способный к функционированию в эукариотической клетке, функционально связанный с нуклеотидной последовательностью, кодирующей последовательность направляющей РНК по п. 1.9. The constructed nucleic acid sequence according to claim 8, further comprising a regulatory element capable of functioning in a eukaryotic cell, operably linked to a nucleotide sequence encoding an RNA guide sequence according to claim 1. 10. Сконструированная последовательность нуклеиновой кислоты по п. 9, в которой регуляторный элемент представляет собой промотер U6 полимеразы III человека. 10. The engineered nucleic acid sequence of claim 9, wherein the regulatory element is a human U6 polymerase III promoter. 11. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота, кодирующая белок Cas9, модифицированный белок Cas9 или гомолог белка Cas9.11. Optimized for the use of human codons, a nucleic acid encoding a Cas9 protein, a modified Cas9 protein, or a Cas9 protein homolog. 12. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, включающая сигнал ядерной локализации.12. Optimized for the use of human codons, the nucleic acid according to claim 11, including a nuclear localization signal. 13. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 12, в которой сигнал ядерной локализации представляет собой С-концевой сигнал ядерной локализации.13. Optimized for the use of human codons, the nucleic acid according to claim 12, wherein the nuclear localization signal is a C-terminal nuclear localization signal. 14. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 13, в которой сигнал ядерной локализации представляет собой С-концевой сигнал ядерной локализации SV40.14. Optimized for the use of human codons, the nucleic acid according to claim 13, wherein the nuclear localization signal is the C-terminal nuclear localization signal SV40. 15. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, включающая функционально присоединенный к ней регуляторный элемент, способный функционировать в эукариотической клетке.15. Optimized taking into account the use of human codons, the nucleic acid according to claim 11, including a regulatory element operably attached thereto, capable of functioning in a eukaryotic cell. 16. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 15, в которой регуляторный элемент представляет собой промотер U6 полимеразы III человека.16. Optimized for the use of human codons, the nucleic acid according to claim 15, wherein the regulatory element is a human U6 polymerase III promoter. 17. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, включающая SEQ ID NO:22. 17. Optimized for the use of human codons, the nucleic acid according to claim 11, including SEQ ID NO: 22. 18. Оптимизированная с учетом использования кодонов человека нуклеиновая кислота по п. 11, кодирующая белок Cas9-нуклеазы-нуль, включающий присоединенный к нему 18. Optimized for the use of human codons, the nucleic acid according to claim 11, encoding a Cas9-nuclease-zero protein, including attached to it a) домен активации или подавления транскрипции;a) a domain of activation or suppression of transcription; b) FokI-нуклеазный домен;b) FokI nuclease domain; c) флуоресцентный белок,c) fluorescent protein d) связывающийся с белками органический флуорофор, связывающийся с нуклеиновыми кислотами органический флуорофор, квантовую точку, молекулярный маяк, эхо-зонд или домен мультивалентного лиганд-связывающего белка, отличного от флуоресцентных молекул, таких как связывающихся с белками или нуклеиновыми кислотами органических флуорофоров, квантовых точек, молекулярных маяков, эхо-зондов или заменителей молекулярных маяков; или d) protein-binding organic fluorophore, nucleic acid-binding organic fluorophore, quantum dot, molecular beacon, echo probe or domain of a multivalent ligand-binding protein other than fluorescent molecules such as organic fluorophores, quantum dot binding to proteins or nucleic acids molecular beacons, echo probes or substitutes for molecular beacons; or e) мультивалентные лиганд-связывающие белки.e) multivalent ligand binding proteins. 19. Система редактирования генома, направляемая РНК, содержащая 19. A genome editing system directed by RNA containing (1) последовательность направляющей РНК или последовательность первой нуклеиновой кислоты, кодирующей последовательность направляющей РНК, и (1) an RNA guide sequence or a first nucleic acid sequence encoding an RNA guide sequence, and (2) фермент Cas, который образует комплекс с последовательностью направляющей РНК, или последовательность второй нуклеиновой кислоты, кодирующей фермент Cas,(2) a Cas enzyme that is complexed with an RNA guide sequence, or a second nucleic acid sequence encoding a Cas enzyme, причем последовательность направляющей РНК содержит спейсерную последовательность, комплементарную целевой последовательности нуклеиновой кислоты и связывающуюся с целевой последовательностью нуклеиновой кислоты, и где направляющая РНК представляет собой слитый транскрипт crРНК-tracrРНК, содержащий от около 100 до около 250 нуклеотидов.wherein the RNA guide sequence contains a spacer sequence complementary to the target nucleic acid sequence and binds to the target nucleic acid sequence, and wherein the RNA guide is a crRNA-tracrRNA fusion transcript containing from about 100 to about 250 nucleotides. 20. Эукариотическая клетка, включающая систему редактирования генома, направляемая РНК, содержащую20. A eukaryotic cell comprising a genome editing system directed by RNA containing (1) последовательность направляющей РНК или последовательность первой нуклеиновой кислоты, кодирующей последовательность направляющей РНК, и(1) an RNA guide sequence or a first nucleic acid sequence encoding an RNA guide sequence, and (2) фермент Cas, который образует комплекс с последовательностью направляющей РНК, или последовательность второй нуклеиновой кислоты, кодирующей фермент Cas,(2) a Cas enzyme that is complexed with an RNA guide sequence, or a second nucleic acid sequence encoding a Cas enzyme, где последовательность направляющей РНК содержит спейсерную последовательность, комплементарную целевой последовательности нуклеиновой кислоты, которая связывается с целевой последовательностью нуклеиновой кислоты, where the sequence of the guide RNA contains a spacer sequence complementary to the target nucleic acid sequence that binds to the target nucleic acid sequence, где последовательность направляющей РНК представляет собой слитый транскрипт crРНК-tracrРНК, включающий от около 100 нуклеотидов до около 250 нуклеотидов.where the sequence of the guide RNA is a fusion transcript of crRNA-tracrRNA, comprising from about 100 nucleotides to about 250 nucleotides. 21. Эукариотическая клетка по п.20, которая представляет собой дрожжевую клетку, растительную клетку, клетку млекопитающего или клетку человека.21. The eukaryotic cell according to claim 20, which is a yeast cell, a plant cell, a mammalian cell or a human cell. 22. Эукариотическая клетка по п.20, где эукариотическая клетка представляет собой стволовую клетку.22. The eukaryotic cell according to claim 20, where the eukaryotic cell is a stem cell. 23. Эукариотическая клетка по п.20, где эукариотическая клетка представляет собой индуцированную плюрипотентную стволовую клетку человека.23. The eukaryotic cell of claim 20, wherein the eukaryotic cell is an induced human pluripotent stem cell. 24. Вирус, включающий нуклеиновую кислоту, кодирующую последовательность направляющей РНК, которая содержит спейсерную последовательность, комплементарную целевой последовательности нуклеиновой кислоты, которая связывается с целевой последовательностью нуклеиновой кислоты, где последовательность направляющей РНК представляет собой слитый транскрипт crРНК-tracrРНК, включающий от около 100 нуклеотидов до около 250 нуклеотидов.24. A virus comprising a nucleic acid encoding an RNA guide sequence that contains a spacer sequence complementary to a target nucleic acid sequence that binds to a target nucleic acid sequence, where the RNA guide sequence is a fusion transcript of crRNA-tracrRNA comprising from about 100 nucleotides to about 250 nucleotides. 25. Вирус по п.24, где вирус представляет собой аденоассоциированный вирус.25. The virus according to paragraph 24, where the virus is an adeno-associated virus. 26. Вирус, содержащий оптимизированную с учетом использования кодонов человека нуклеиновую кислоту, кодирующую белок Cas9, модифицированный белок Cas9 или гомолог белка Cas9.26. A virus containing a nucleic acid optimized for human codons that encodes a Cas9 protein, a modified Cas9 protein, or a Cas9 protein homolog. 27. Вирус по п.26, где вирус представляет собой аденоассоциированный вирус.27. The virus of claim 26, wherein the virus is an adeno-associated virus.
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